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V Kren

Publications and source records attributed to V Kren.

At least 91 records · Page 5Linked to original sources
PubMed1997

Quantitative trait loci for cellular defects in glucose and fatty acid metabolism in hypertensive rats.

Coronary heart disease, hypertension, non-insulin-dependent diabetes and obesity are major causes of ill health in industrial societies. Disturbances of carbohydrate and lipid metabolism are a common feature of these disorders. The bases for these disturbances and their roles in disease pathogenesis are poorly understood. The spontaneously hypertensive rat (SHR), a widely used animal model of essential hypertension, has a global defect in insulin action on glucose metabolism and shows reduced catecholamine action on lipolysis in fat cells. In our study we used cellular defects in carbohydrate and lipid metabolism to dissect the genetics of defective insulin and catecholamine action in the SHR strain. In a genome screen for loci linked to insulin and catecholamine action, we identified two quantitative trait loci (QTLs) for defective insulin action, on chromosome 4 and 12. We found that the major (and perhaps only) genetic determinant of defective control of lipolysis in SHR maps to the same region of chromosome 4. These linkage results were ascertained in at least two independent crosses. As the SHR strain manifests many of the defining features of human metabolic Syndrome X, in which hypertension associates with insulin resistance, dyslipidaemia and abdominal obesity, the identification of genes for defective insulin and catecholamine action in SHR may facilitate gene identification in this syndrome and in related human conditions, such as type-2 diabetes and familial combined hyperlipidaemia.

Animals↗
PubMed1997

Genetic isolation of a chromosome 1 region affecting blood pressure in the spontaneously hypertensive rat.

Recent linkage studies in the spontaneously hypertensive rat (SHR) suggest that a blood pressure regulatory gene or genes may be located on rat chromosome 1q. To investigate this possibility, we replaced a region of chromosome 1 in the SHR (defined by the markers D1Mit3 and Igf2) with the corresponding chromosome segment from the normotensive Brown-Norway (BN) strain. In male SHR congenic rats carrying the transferred BN chromosome segment, 24-hour average systolic and diastolic blood pressures were significantly lower than in male progenitor SHR. Polymerase chain reaction genotyping using 60 polymorphic microsatellite markers dispersed throughout the genome confirmed the congenic status of the new strain designated SHR.BN-D1Mit3/Igf2. These findings provide direct evidence that a blood pressure regulatory gene exists on the differential segment of chromosome 1 that is sufficient to decrease blood pressure in the SHR. The SHR.BN-D1Mit3/Igf2 congenic strain represents an important new model for fine mapping and characterization of genes on chromosome 1 involved in the pathogenesis of spontaneous hypertension.

Animals↗
PubMed1997

Neuroimmunomodulation of natural killer (NK) cells by ergot alkaloid derivatives.

Ergot alkaloids (EAs), products of Claviceps spp., are widely used in various fields of clinical medicine (neurology, psychiatry, endocrinology). In the present work we studied the neuroimmunomodulative effect of EAs on activation of NK cells and their signalling pathways. Furthermore, the killing capability of rat NK cells in vitro was examined in the presence of glycosidic derivatives of elymoclavine, agroclavine, and liposome-encapsulated EAs. The engagement of appropriate NK cell membrane receptors by EAs cause an indirect enhancement of adenylyl cyclase system through inhibition of G-protein al,2-subunit (up to 50 % of control values). All of the tested EAs enhanced the rat NK cell-mediated cytotoxic activity in vitro, particularly against target cells of astrocyte origin (C-6 glioma). The present results argue for a possible EA immunomodulatory role of cell-mediated immunity in tumour regression processes.

Animals↗
PubMed1996

Use of AFLP markers for gene mapping and QTL detection in the rat.

The AFLP technique is a new DNA marker technology based on the selective amplification of restriction fragments. Multiple polymorphic markers are simultaneously produced and can be tested in one PCR. No prior information on genomic DNA sequences is needed. In the current study, we contribute 18 AFLP markers to the linkage map of the rat. Seven AFLP markers were assigned to specific chromosomes by analysis of a (BN x ACI)F1 x ACI backcross progeny. Another 11 AFLP markers were mapped by using a panel of the H x B/B x H recombinant inbred (RI) strains. Genotypes of these AFLP markers were also tested for correlations with some blood pressure phenotypes in the RI strains. Suggestive correlation was found between the mean arterial pressure and two closely linked AFLP markers located on chromosome 20. The current study illustrates the value of AFLP markers for the construction of linkage maps and the detection of quantitative trait loci.

Animals↗
PubMed1996

Quantitative trait loci influencing cholesterol and phospholipid phenotypes map to chromosomes that contain genes regulating blood pressure in the spontaneously hypertensive rat.

The frequent coincidence of hypertension and dyslipidemia suggests that related genetic factors might underlie these common risk factors for cardiovascular disease. To investigate whether quantitative trait loci (QTLs) regulating lipid levels map to chromosomes known to contain genes regulating blood pressure, we used a genome scanning approach to map QTLs influencing cholesterol and phospholipid phenotypes in a large set of recombinant inbred strains and in congenic strains derived from the spontaneously hypertensive rat and normotensive Brown-Norway (BN.Lx) rat fed normal and high cholesterol diets. QTLs regulating lipid phenotypes were mapped by scanning the genome with 534 genetic markers. A significant relationship (P < 0.00006) was found between basal HDL2 cholesterol levels and the D19Mit2 marker on chromosome 19. Analysis of congenic strains of spontaneously hypertensive rat indicated that QTLs regulating postdietary lipid phenotypes exist also on chromosomes 8 and 20. Previous studies in the recombinant inbred and congenic strains have demonstrated the presence of blood pressure regulatory genes in corresponding segments of chromosomes 8, 19, and 20. These findings provide support for the hypothesis that blood pressure and certain lipid subfractions can be modulated by linked genes or perhaps even the same genes.

Animals↗
PubMed1996

A genetic linkage map of the rat derived from recombinant inbred strains.

We have constructed a genetic linkage map in the rat by analyzing the strain distribution patterns of 500 genetic markers in a large set of recombinant inbred strains derived from the spontaneously hypertensive rat and the Brown-Norway rat (HXB and BXH recombinant inbred strains). 454 of the markers could be assigned to specific chromosomes, and the amount of genome covered by the mapped markers was estimated to be 1151 centimorgans. By including a variety of morphologic, biochemical, immunogenetic, and molecular markers, the current map integrates and extends existing linkage data and should facilitate rat gene mapping and genetic studies of hypertension and other complex phenotypes of interest in the HXB and BXH recombinant inbred strains.

Animals↗
PubMed1996

Ergot alkaloid glycosides with immunomodulatory activities.

New glycosides derived from ergot alkaloids elymoclavine and DH-lysergol were synthesized by chemoenzymatic methods. beta-Glucosides were obtained either by chemical method or by transglycosylation (glycosidase from Aspergillus oryzae), lactosides were prepared by further extension of carbohydrate chain using beta-1,4-galactosyltransferase (bovine milk) and alpha-5-N-acetylneuraminyl-(2-->6)-beta-D-galactopyranosyl-(l-->4)-2- acetamido-2-deoxy-beta-D-glucopyranosyl-(1-->O)-elymoclavine was prepared using alpha-2,6-sialyltransferase (rat liver). Immunomodulatory activity of elymoclavine and 9,10-dihydrolysergol and their glycosylated derivatives on natural killer (NK) cell-mediated cytotoxicity of human resting and activated human peripheral blood mononuclear cells (PBMC) was investigated. Addition of ergot alkaloid glycosides to the mixtures of effector and target cells potentiated the PBMC cytotoxicity against both NK-sensitive and -resistant target cells. The glycoconjugates of elymoclavine enhanced cytotoxicity of PBMC against NK-resistant target cells. The glycoconjugates of DH-lysergol potentiated NK cytotoxicity of PBMC against NK-sensitive target cells.

Adjuvants, Immunologic↗
PubMed1996

HSP27 locus cosegregates with left ventricular mass independently of blood pressure.

Left ventricular hypertrophy remains a significant clinical problem and a predictor of fatal outcome in hypertension. Blood pressure per se and environmental modifiers including stress affect cardiac mass. Heat shock proteins are involved in the stress response as well as in the regulation of cardiac growth and cytoprotection. The present study evaluates heat shock protein 27 as a locus marker or candidate gene of cardiac hypertrophy in hypertension. The spontaneously hypertensive rat allele of heat shock protein 27 was associated with about a 6% increase in relative left ventricular weight (P = .0112) in 30 recombinant inbred strains from crosses of Brown Norway and spontaneously hypertensive rats. In 336 F2 crosses of spontaneously hypertensive and Wistar-Kyoto rats, the hypertensive allele was dominant and cosegregated with a similar 6% increase in the ratio of left ventricular weight to body weight (P = .0058) in rats fed a normal salt diet, but its contribution to left ventricular weight decreased in rats kept on a high salt diet. The contribution of the heat shock protein 27 allele was independent of blood pressure. We suggest that heat shock protein 27 represents a candidate gene/locus marker of cardiac hypertrophy in hypertension.

Alleles↗
PubMed1996

Recombinant inbred and congenic strains for mapping of genes that are responsible for spontaneous hypertension and other risk factors of cardiovascular disease.

The spontaneously hypertensive rat (SHR) is the most widely used animal model of human essential hypertension. In the SHR strain, as in humans, the high blood pressure is determined multifactorially. Analysis of genetically segregating populations, derived from SHR and normotensive inbred strains, enabled localization of quantitative trait loci (QTLs) responsible for blood pressure regulation on several rat chromosomes. Analysis of specialized strains, congenic and recombinant inbred (RI) strains, helped to analyze some of these mapping results in detail: (1) analysis of congenic strains provided definitive evidence for the presence of blood pressure regulatory genes on chromosomes 8 and 13 and will enable mapping of responsible genes to limited segments of differential chromosomes, (2) the RI strains were shown to be especially useful for genome scanning studies of complex traits and for correlation analysis of blood pressure and other risk factors of cardiovascular disease such as cardiac hypertrophy, dyslipidemia, and insulin resistance.

Animals↗
PubMed1996

Recombinant inbred and congenic strains of the rat for genetic analysis of limb morphogenesis.

Recombinant inbred (RI) and congenic strains carrying the polydactyly-luxate syndrome (PLS) provide an experimental model for the analysis of polygenic control of limb development. PLS is determined by a major gene Lx whose phenotypic expression is strongly influenced by the genetic background upon which it operates. The morphometric analysis of the skeleton of front and hind legs has been carried out. The morphotypes of PLS in RI strains exhibit a continuous variability and transgressive variation compared to BN.Lx and SHR.Lx morphotypes, which strongly indicates the polygenic effects on PLS manifestation. Quantitative trait loci (QTL) were searched for through correlation of genetic markers and morphometric traits. The association analysis revealed statistically significant correlations (P < 0.0003) of morphometric traits with two markers on chromosome 4 (Il6 and A2m) associated with the number of front feet and hind feet phalanges, respectively, one marker on chromosome 7 (D7Mit17) associated with the tibia length, and the somatostatin gene on chromosome 11 associated with the number of front feet phalanges. In addition, suggestive associations of morphometric traits with markers on further nine chromosomes have been found (correlation coefficients ranging from 0.5 to 0.6). The verification of all these findings is in progress by means of double congenic strains which, in addition to the Lx gene, carry differential chromosome segments with putative modifiers.

Animals↗
PubMed1996

The teratogenic action of retinoic acid in rat congenic and recombinant inbred strains.

The teratogenic effect of all-trans retinoic acid (RA) was tested in the system of congenic and recombinant inbred (RI) strains of the laboratory rat carrying the mutant Lx allele which determines the polydactyly-luxate syndrome. It was demonstrated that the teratogenic effect of RA is influenced by both the genotype at the Lx locus and the modifying genes. The dose of 100 mg/kg administered by gavage on day 11 of pregnancy induced a statistically significant incidence of preaxial polydactyly in hind limbs of LEW/BN, +/Lx foetuses heterozygous in the mutant allele, whereas no specific limb defects were noted in foetuses LEW/BN, +/+ without the mutant allele. In foetuses homozygous in the mutant allele LEW/BN, Lx/Lx and SHR/BXH2, Lx/Lx, RA conversely induced a significant reduction in the number of toes on the preaxial side of hind limbs and a reduction of the zeugopodium, mostly the tibia. Reduction changes were more marked in SHR/BXH2, Lx/Lx foetuses, in which the tibia was entirely missing and sirenomelia was found. The foetuses in this group have in their genetic background a combination of modifiers that are responsible for oligodactyly and tibial hemimelia in the BXH2 strain. On the basis of continuing mapping of the rat genome, the testing of RA in the system of RI and congenic strains will be utilized for identification of so far hypothetical genes involved in morphogenesis.

Animals↗